What is the role of gene therapy in the treatment of severe combined immunodeficiency (SCID)?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

Gene therapy is a viable option for patients with XL-SCID or ADA-deficient SCID who have no HLA-identical sibling. Treatment is optimally provided early enough to reduce the risks of failed gene transduction and leukemia. Murine studies suggest that gene therapy may work for JAK3 and RAG2 mutations as well. Several gene therapy clinical trials have been utilized, including a CD34+ cells transduced with retroviral vector-based gene therapy (Strimvelis; Orchard Therapeutics) that was approved in Europe in 2016 and is currently in phase 3 trials in the US for ADA-SCID. [46, 47, 48, 49]

An investigational ex vivo autologous gene therapy, simoladagene autotemcel (OTL-101; Orchard Therapeutics), is in phase 3 clinical trials as of May 2020 for ADA-SCID in the US. [50]   

A clinical trial of gene therapy for XL-SCID found that in cases of successful gene insertion, functional T cells developed within 18 weeks and were detectable as long as 5 years later. [51] Adverse events have included failure of gene insertion and acute lymphoblastic leukemia due to aberrant insertion within the LMO-2 gene, both of which occurred in older patients. Other studies have confirmed the risk for leukemia in patients who underwent gene therapy and attempts are underway to minimize it.

ADA deficiency was the first form of SCID for which gene therapy was attempted, and efficacy has been reported; it remains in the experimental phase. Although some long-term benefits of gene therapy have been reported for ADA-deficient patients with SCID, complications have arisen in some cases of gene therapy in patients with common γ chain deficiency.

The development of leukemia is a complication of gene therapy and appears to be related to the site of insertion of the transgene. Some suggest that better outcomes may occur with different vectors or more specific insertion sites. [52] A greater risk of cognitive abnormalities and emotional and behavioral problems has also been reported in patients with ADA-deficient SCID who received long-term enzyme replacement therapy. [53]


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